1-241500602-TGAGAGAGAGAGAGAGAGA-TGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGA

Variant names:

• chr1-241500602-T-TGAGAGAGAGAGAGAGAGA
• rs144131869
• NM_000143.4:c.1237-30_1237-13dupTCTCTCTCTCTCTCTCTC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000143.4(FH):​c.1237-30_1237-13dupTCTCTCTCTCTCTCTCTC variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (4 hom., cov: 0)
  • Exomes 𝑓: 0.0014 (9 hom.)
  • Failed GnomAD Quality Control
• Consequence: FH NM_000143.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.993
• Publications: 5 publications found

Genes affected

FH (HGNC:3700): (fumarate hydratase) The protein encoded by this gene is an enzymatic component of the tricarboxylic acid (TCA) cycle, or Krebs cycle, and catalyzes the formation of L-malate from fumarate. It exists in both a cytosolic form and an N-terminal extended form, differing only in the translation start site used. The N-terminal extended form is targeted to the mitochondrion, where the removal of the extension generates the same form as in the cytoplasm. It is similar to some thermostable class II fumarases and functions as a homotetramer. Mutations in this gene can cause fumarase deficiency and lead to progressive encephalopathy. [provided by RefSeq, Jul 2008]

FH Gene-Disease associations (from GenCC):

• hereditary leiomyomatosis and renal cell cancer

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• fumaric aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• pheochromocytoma-paraganglioma

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• leiomyosarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 1-241500602-T-TGAGAGAGAGAGAGAGAGA is Benign according to our data. Variant chr1-241500602-T-TGAGAGAGAGAGAGAGAGA is described in ClinVar as Likely_benign. ClinVar VariationId is 1692239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00398 (533/133824) while in subpopulation AFR AF = 0.00455 (159/34946). AF 95% confidence interval is 0.00397. There are 4 homozygotes in GnomAd4. There are 239 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000143.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FH	NM_000143.4	MANE Select	c.1237-30_1237-13dupTCTCTCTCTCTCTCTCTC		intron	N/A	NP_000134.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FH	ENST00000366560.4	TSL:1 MANE Select	c.1237-30_1237-13dupTCTCTCTCTCTCTCTCTC		intron	N/A	ENSP00000355518.4
	FH	ENST00000682567.1		n.4607_4624dupTCTCTCTCTCTCTCTCTC		non_coding_transcript_exon	Exon 7 of 8
	FH	ENST00000683521.1		c.1237-30_1237-13dupTCTCTCTCTCTCTCTCTC		intron	N/A	ENSP00000506864.1

Frequencies

GnomAD3 genomes AF: 0.00399 AC: 533 AN: 133734 Hom.: 4 Cov.: 0

Gnomad AFR AF: 0.00456

Gnomad AMI AF: 0.00462

Gnomad AMR AF: 0.00297

Gnomad ASJ AF: 0.0162

Gnomad EAS AF: 0.000651

Gnomad SAS AF: 0.00197

Gnomad FIN AF: 0.00508

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00354

Gnomad OTH AF: 0.00281

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00140 AC: 1904 AN: 1355580 Hom.: 9 Cov.: 48 AF XY: 0.00134 AC XY: 906 AN XY: 674866

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00278 AC: 87 AN: 31244

American (AMR) AF: 0.000724 AC: 30 AN: 41426

Ashkenazi Jewish (ASJ) AF: 0.00431 AC: 105 AN: 24378

East Asian (EAS) AF: 0.000186 AC: 7 AN: 37712

South Asian (SAS) AF: 0.000421 AC: 34 AN: 80746

European-Finnish (FIN) AF: 0.00307 AC: 122 AN: 39684

Middle Eastern (MID) AF: 0.000951 AC: 4 AN: 4204

European-Non Finnish (NFE) AF: 0.00136 AC: 1413 AN: 1039956

Other (OTH) AF: 0.00181 AC: 102 AN: 56230

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00398 AC: 533 AN: 133824 Hom.: 4 Cov.: 0 AF XY: 0.00374 AC XY: 239 AN XY: 63840

African (AFR) AF: 0.00455 AC: 159 AN: 34946

American (AMR) AF: 0.00296 AC: 39 AN: 13158

Ashkenazi Jewish (ASJ) AF: 0.0162 AC: 53 AN: 3274

East Asian (EAS) AF: 0.000652 AC: 3 AN: 4600

South Asian (SAS) AF: 0.00197 AC: 8 AN: 4054

European-Finnish (FIN) AF: 0.00508 AC: 36 AN: 7090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 270

European-Non Finnish (NFE) AF: 0.00354 AC: 226 AN: 63770

Other (OTH) AF: 0.00278 AC: 5 AN: 1796

Alfa AF: 0.00 Hom.: 226

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:1

Jun 07, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

FH-related disorder Benign:1

Dec 19, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.99
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs144131869; hg19: chr1-241663902;